Molina David, Pérez-Beteta Julián, Martínez-González Alicia, Sepúlveda Juan M, Peralta Sergi, Gil-Gil Miguel J, Reynes Gaspar, Herrero Ana, De Las Peñas Ramón, Luque Raquel, Capellades Jaume, Balaña Carmen, Pérez-García Víctor M
Laboratory of Mathematical Oncology (MôLAB), Instituto de Matemática Aplicada a la Ciencia y la Ingeniería, Edificio Politécnico, Avda. Camilo José Cela 3, Universidad de Castilla-La Mancha, 13071 Ciudad Real, Spain.
Medical Oncology Service, Hospital Universitario, 12 de Octubre, Madrid, Spain.
PLoS One. 2016 Aug 24;11(8):e0161484. doi: 10.1371/journal.pone.0161484. eCollection 2016.
Antiangiogenic therapies for glioblastoma (GBM) such as bevacizumab (BVZ), have been unable to extend survival in large patient cohorts. However, a subset of patients having angiogenesis-dependent tumors might benefit from these therapies. Currently, there are no biomarkers allowing to discriminate responders from non-responders before the start of the therapy.
40 patients from the randomized GENOM009 study complied the inclusion criteria (quality of images, clinical data available). Of those, 23 patients received first line temozolomide (TMZ) for eight weeks and then concomitant radiotherapy and TMZ. 17 patients received BVZ+TMZ for seven weeks and then added radiotherapy to the treatment. Clinical variables were collected, tumors segmented and several geometrical measures computed including: Contrast enhancing (CE), necrotic, and total volumes; equivalent spherical CE width; several geometric measures of the CE 'rim' geometry and a set of image texture measures. The significance of the results was studied using Kaplan-Meier and Cox proportional hazards analysis. Correlations were assessed using Spearman correlation coefficients.
Kaplan-Meier and Cox proportional hazards analysis showed that total, CE and inner volume (p = 0.019, HR = 4.258) and geometric heterogeneity of the CE areas (p = 0.011, HR = 3.931) were significant parameters identifying response to BVZ. The group of patients with either regular CE areas (small geometric heterogeneity, median difference survival 15.88 months, p = 0.011) or those with small necrotic volume (median survival difference 14.50 months, p = 0.047) benefited substantially from BVZ.
Imaging biomarkers related to the irregularity of contrast enhancing areas and the necrotic volume were able to discriminate GBM patients with a substantial survival benefit from BVZ. A prospective study is needed to validate our results.
胶质母细胞瘤（GBM）的抗血管生成疗法，如贝伐单抗（BVZ），在大量患者队列中未能延长生存期。然而，一部分具有血管生成依赖性肿瘤的患者可能会从这些疗法中获益。目前，尚无生物标志物能够在治疗开始前区分反应者和无反应者。
随机GENOM009研究中的40名患者符合纳入标准（图像质量、可获得临床数据）。其中，23名患者接受了为期八周的一线替莫唑胺（TMZ）治疗，然后接受同步放疗和TMZ治疗。17名患者接受了为期七周的BVZ+TMZ治疗，然后在治疗中加入放疗。收集临床变量，对肿瘤进行分割，并计算了几种几何测量值，包括：强化（CE）、坏死和总体积；等效球形CE宽度；CE“边缘”几何形状的几种几何测量值以及一组图像纹理测量值。使用Kaplan-Meier和Cox比例风险分析研究结果的显著性。使用Spearman相关系数评估相关性。
Kaplan-Meier和Cox比例风险分析表明，总体积、CE体积和内部体积（p = 0.019，HR = 4.258）以及CE区域的几何异质性（p = 0.011，HR = 3.931）是识别对BVZ反应的重要参数。CE区域规则（几何异质性小，中位生存差异15.88个月，p = 0.011）或坏死体积小（中位生存差异14.50个月，p = 0.047）的患者组从BVZ中获益显著。
与强化区域不规则性和坏死体积相关的影像学生物标志物能够区分从BVZ中获得显著生存获益的GBM患者。需要进行前瞻性研究来验证我们的结果。
